This application is the National Stage Application of PCT/JP00/05851 filed Aug. 30, 2000.
The present invention relates to a process for preparing a 3-alkenylcephem compound or 3-norcephem compound of the formula (3).
The 3-alkenylcephem compound or 3-norcephem compound of the formula (3) has the basic skeleton of a nonnatural antibiotic substance and is an important intermediate for preparing useful antimicrobial drugs having a wide antibacterial spectrum, such as cefixime and ceftibuten which are oral antibiotics generally in wide use (Katsuharu Sakai, xe2x80x9cHandbook of Recent Antibiotics,xe2x80x9d 9th ed., pp. 83 and 85, 1994).
Already known as processes for preparing 3-alkenylcephem compounds are a process for subjecting a 3-halogenated methylcephem compound to Wittig reaction (e.g., JP-A-263990/1986), a process for introducing vinyl into a 3-sulfonyloxycephem compound utilizing a metallic catalyst [Tetrahedron Letters, 29, 6043 (1988), 31, 3389 (1990), 32, 4073 (1991), Journal of Organic Chemistry, 55, 5833 (1990)], a process wherein an allenyl xcex2-lactam compound or halogenated xcex2-lactam compound is used as the starting material [Tetrahedron Letters, 33, 7029 (1992), Journal of Organic Chemistry, 59, 4956 (1994), Synlett, 774 (1999)], etc.
However, the Wittig reaction mentioned first inevitably requires the treatment of a very large quantity of phosphorus by-product to be discarded since the reaction mechanism invariably forms a trialkyl or triaryl phosphine oxide in an amount equimolar to the starting material. The process for introducing vinyl into a 3-sulfonyloxycephem compound utilizing a metallic catalyst has a great industrial disadvantage in that the process not only requires the use of an expensive reagent which is sensitive to water in preparing the starting material but also requires an alkenyl tin compound or vinyl cuprate compound which must be used but is harmful to the reagent for alkenylation.
The process wherein an allenyl xcex2-lactam compound is used as the starting material is difficult to practice industrially because the allenyl xcex2-lactam compound serving as the starting compound is unstable and further because a combination of copper chloride and vinyltributyl tin or vinyl cuprate prepared from vinyltributyl tin is used as the reaction reagent.
The process wherein a halogenated xcex2-lactam compound is used as the starting material has the problem of necessitating a multistep reaction procedure for preparing the starting material, requires the use of an organotin compound as an alkenylation reagent for the reaction, and still remains to be improved for realization.
Although these conventional techniques have found application to the preparation not only of 3-vinylcephem compounds but also of 3-alkenylcephem compounds, substantial problems have yet to be overcome.
On the other hand, reports have already been made on a process for preparing 3-norcephem compounds wherein zinc is caused to act, for example, on a 3-halocephem compound or 3-sulfonyloxycephem compound as the starting compound ([JP-A-59186/1977 and Recent Advances in the Chemistry of xcex2-Lactam Antibiotics, 170(1977), and Pure and Appl. Chem., 59, 1041(1987)]. However, this process requires the use of a large amount of acetic acid, formic acid or trifluoroacetic acid and is difficult to practice.
Reports are also made on a process comprising catalytically hydrogenating first a 3-hydroxycephem compound serving as the starting material to obtain a 3-hydroxycepham compound and thereafter subjecting the compound to 1,2-elimination reaction with use of a haloformic acid ester/base to obtain a 3-norcephem compound (JP-A-213785/1983 and JP-A-34714/1983, or Pure and Appl. Chem., 59, 1041 (1987)]. This process requires the two steps of catalytic hydrogenation and 1,2-elimination reaction for the preparation of the desired compound and can not be a practically useful process.
A report is also made on a process wherein 3-formylcephem is used as the starting material, and a process wherein the Wittig reaction is used (Chemistry and Biology of xcex2-Lactam Antibiotics, Penicillins and Cephalosporins, Vol. 1, 170), whereas the starting materials for both of these processes are compounds which are very difficult to obtain, the former requires the use of an expensive rhodium complex, and the latter has the problem that the Wittig reaction utilized forms a large amount of phosphorus by-product which must be disposed of.
An object of the present invention is to provide an industrially feasible process for preparing a 3-alkenylcephem compound or 3-norcephem compound from a 3-cephem compound of the formula (1) and serving as the starting material.
Stated more specifically, in a process for preparing with ease a 3-alkenylcephem compound or 3-norcephem compound by causing an alkenyl halide of the formula (2), a nickel catalyst, a metal up to xe2x88x920.3 (V/SCE) in standard oxidation reduction potential and a compound of a metal having a higher standard oxidation reduction potential than the metal to act on a 3-cephem compound, the invention provides a novel technique capable of selectively producing one of the 3-alkenylcephem compound and the 3-norcephem compound merely by changing the solvent to be used in the process.
The present invention provides a process for selectively preparing a 3-alkenylcephem compound or 3-norcephem compound from a 3-cephem compound of the formula (1) and serving as the starting material.
The invention provides a process for preparing a 3-alkenylcephem compound or 3-norcephem compound of the formula (3) characterized in that an alkenyl halide of the formula (2), a nickel catalyst, a metal up to xe2x88x920.3 (V/SCE) in standard oxidation reduction potential and a compound of a metal having a higher standard oxidation reduction potential than the metal are caused to act on a 3-cephem compound of the formula (1) in a solvent 
wherein R1 is a hydrogen atom, halogen atom, amino or protected amino, R2 is a hydrogen atom, halogen atom, lower alkoxyl, lower acyl, hydroxyl, protected hydroxyl, or lower alkyl having or not having hydroxyl or protected hydroxyl as a substituent, R3 is a hydrogen atom or carboxylic acid protective group, and X is a halogen atom, lower alkylsulfonyloxy having or not having a substituent or an arylsulfonyloxy having or not having a substituent
R4xe2x80x94Yxe2x80x83xe2x80x83(2)
wherein R4 is 1-alkenyl having or not having a substituent, and Y is a halogen atom 
wherein R1, R2 and R3 are as defined above, and R5 is a hydrogen atom or 1-alkenyl having or not having a substituent.
According to the present invention, a 3-alkenylcephem compound can be prepared selectively with a high purity in a high yield by causing an alkenylation reagent, which are relatively safe to the human body and have high universal usefulness, to act on a 3-cephem compound having high stability, readily available and represented by the formula (1). Furthermore, a 3-norcephem compound can be selectively prepared with a high purity and in a high yield by changing the reaction condition. Thus one of the two kinds of nonnatural cephem skeletons can be readily prepared selectively.
Examples of groups referred to in the present invention are as follows. Unless otherwise specified, the term xe2x80x9chalogen atomxe2x80x9d as used herein refers to fluorine, chlorine, bromine or iodine, and the term xe2x80x9clower alkylxe2x80x9d means a straight-chain or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
The term xe2x80x9carylxe2x80x9d means, for example, phenyl, naphthyl or the like.
Exemplary of the protected amino represented by R1 are amido groups such as phenoxyacetamido, p-methylphenoxyacetamido, p-methoxyphenoxyacetamido, p-chlorophenoxyacetamido, p-bromophenoxyacetamido, phenylacetamido, p-methylphenylacetamido, p-methoxyphenylacetamido, p-chlorophenylacetamido, p-bromophenylacetamido, phenylmonochloroacetamido, phenyldichloroacetamido, phenylhydroxyacetamido, thienylacetamido, phenylacetoxyacetamido, xcex1-oxophenylacetamido, benzamido, p-methylbenzamido, p-methoxybenzamido, p-chlorobenzamido, p-bromobenzamido, phenylglycylamido, phenylglycylamido having protected amino, p-hydroxyphenylglycylamido, p-hydroxyphenylglycylamido having protected amino and/or protected hydroxyl, etc.; imido groups such as phthalimido, nitrophthalimido, etc., in addition to the groups disclosed in Theodora W. Greene, 1981, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (hereinafter referred to merely as the xe2x80x9cliteraturexe2x80x9d), Chap. 7 (pp. 218xcx9c287). Examples of protective groups for the amino of phenylglycylamido group and p-hydroxyphenylglycylamido group are those disclosed in the literature, Chap. 7 (pp. 218xcx9c287). Examples of protective groups for the hydroxyl of p-hydroxyphenylglycylamido group are those disclosed in the literature, Chap.2 (pp. 10xcx9c72).
Exemplary of the lower alkoxyl represented by R2 are straight-chain or branched C1xcx9c4 alkoxyl groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy groups.
Exemplary of the lower acyl represented by R2 are straight-chain or branched C1xcx9c4 acyl groups such as formyl, acetyl, propionyl, butyryl and isobutyryl.
Examples of protective groups for the protected hydroxyl in the lower alkyl represented by R2 and substituted with hydroxyl or protected hydroxyl, and for the protected hydroxyl represented by R are those disclosed in the literature, Chap. 2 (pp. 10xcx9c72). The substituted lower alkyl represented by R2 may have as its substituent(s) one or at least two same or different groups selected from among hydroxyl and the protected hydroxyl groups. Such substituent(s) may be positioned on at least one carbon atom of the alkyl.
Exemplary of the carboxylic acid protecting group represented by R3 are allyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, trichloromethyl, trichloroethyl, tert-butyl, and those disclosed in the literature, Chap. 5 (pp. 152xcx9c192).
Examples of substituents for the 1-alkenyl which is represented by R4 and R5 and which may have a substituent can be a halogen atom, hydroxyl, nitro, cyano, aryl, lower alkyl, amino, mono lower alkylamino, di lower alkylamino, mercapto, alkylthio or arylthio represented by the group R6Sxe2x80x94 (wherein R6 is lower alkyl or aryl), formyloxy, acyloxy represented by the group R6COOxe2x80x94 (wherein R6 is as defined above), formyl, acyl represented by the group R6COxe2x80x94 (wherein R6 is as defined above), alkoxyl or aryloxy represented by the group R6Oxe2x80x94 (wherein R6 is as defined above), carboxyl, alkoxycarbonyl or aryloxycarbonyl represented by the group R6OCOxe2x80x94 (wherein R6 is as defined above), etc. The 1-alkenyl represented by R4 and R5 may have on the same carbon atom or different carbon atoms one or more substituents which are selected from among the above substituents and which may be the same or different.
Examples of lower alkylsulfonyloxy or substituted lower alkylsulfonyloxy represented by X are methanesulfonyloxy, trifluoromethanesulfonyloxy and trichloromethanesulfonyloxy. Examples of arylsulfonyloxy or substituted arylsulfonyloxy are benzenesulfonyloxy and toluenesulfonyloxy.
The 3-cephem compound of the formula (1) and to be used as the starting material is prepared, for example, by one of the following processes disclosed in literature, depending on the kind of X.
When X is a halogen atom, the compound can be prepared by reacting a reactive chloro compound (such as phosphorus trichloride or phosphorus oxychloride) with a 3-hydroxycephem compound (I) serving as the starting material in dimethylformamide (see JP-A-116095/1974) 
wherein R1, R2 and R3 are as defined above.
When X is lower alkylsulfonyloxy which may have a substituent or arylsulfonyloxy which may have a substituent, the compound can be prepared by reacting a 3-hydroxycephem compound of the formula (I) with a lower alkylsulfonic anhydride which may have a substituent or an arylsulfonic anhydride which may have a substituent [Journal of Organic Chemistry, 54, 4962 (1989)].
According to the present invention, an alkenyl halide of the formula (2), a nickel catalyst, a metal up to xe2x88x920.3 (V/SCE) in standard oxidation reduction potential and a compound of a metal having a higher standard oxidation reduction potential than the metal are caused to act on the 3-cephem compound of the formula (1) and prepared by the above process, in an organic solvent, whereby a 3-alkenylcephem compound of the formula (3) [the formula (3a) given below] can be prepared with ease.
Alternatively, a 3-norcephem compound [of the formula (3b) given below] can be obtained by replacing the solvent with a water-containing organic solvent under the same condition 
wherein R1, R2, R3 and R4 are as defined above.
When the solvent used is a water-containing solvent, the 3-norcephem compound of the formula (3b) is obtained presumably because addition of a hydrogen ion occurs before the anion at the 3-position of the compound (1) resulting from reduction undergoes a coupling reaction with the compound (2).
Examples of 1-alkenyl halide compounds of the formula (2) for use in the present invention are vinyl iodide, vinyl chloride, vinyl bromide, 1-cis-propenyl bromide, 1-butenyl bromide, 2-methyl-1-propenyl bromide, 1-methyl-1-propenyl bromide, 1,2-dimethyl-1-propenyl bromide, 3-phenyl-1-propenyl bromide, etc. The compound of the formula (2) is used usually in an amount of 1 to 10 moles, preferably 1 to 4 moles, per mole of the compound of the formula (1).
Examples of nickel catalysts usable are nickel fluoride, nickel chloride, nickel bromide, nickel iodide, nickel nitrate, nickel sulfate, nickel perchlorate, nickel acetate and like nickel salts of fatty acids, tetraethylammoniumnickel(II) tetrachloride, tetraethylammoniumnickel (II) tetrabromide, hexamminenickel (II) chloride, hexamminenickel(II) bromide, dinitrotetramminenickel(II), tris(ethylenediamine)nickel(II) chloride, tris(ethylenediamine)nickel(II) sulfate, dinitrobis(ethylenediamine)nickel(II), bis(N,N-dimethylethylenediamine)nickel(II) perchlorate, dichloro(bipyridyl)nickel(II), dibromo(bipyridyl)nickel(II), chloro(cyclopentadienyl)(triphenylphosphine)nickel(II), dichloro(triphenylphosphine)nickel(II), dibromo(triphenylphosphine)nickel(II) and like nickel(II) complexes, tetrakis(triphenylphosphine)nickel(0), tris(triphenylphosphine)nickel(0), nickel(0) acetylacetonate, nickel(0) hexafluoroacetylacetonate and like nickel(0) complexes. These metallic compounds may be used singly, or at least two of them are usable in mixture.
It is desirable to use the catalyst usually in an amount of 0.01 to 10 moles, preferably 0.1 to 1 mole, per mole of the compound of the formula (1).
Examples of metals having a standard oxidation-reduction potential of up to xe2x88x920.3 (V/SCE) are magnesium, aluminum, manganese, zinc, iron, tin, lead, etc., among which aluminum is desirable to use. The shape of these metals is not limited particularly but can be any of a wide variety of forms such as powder, plate, foil, lump and wire. Preferably, the metal to be used is in the form of a powder or foil. The particle size of the powdery metal is preferably about 10 to about 300 mesh although variable over a wide range. These metals are used usually in an amount of about 1 to about 50 moles, preferably about 1 to about 10 moles, per mole of the compound of the formula (1).
In case the metal is used less than one mole per mole of the compound of the formula (1), unreacted compound (1) remains which is undesirable to cause decrease in yield and purity of the desired compound.
Examples of metal compounds having a higher standard oxidation-reduction potential than the above metals are lead compounds (such as lead fluoride, lead chloride, lead bromide, lead iodide, lead nitrate, lead sulfate, lead perchlorate, lead borate, lead carbonate, lead phosphate and like inorganic salts of lead, lead acetate, lead oxalate, lead stearate and like fatty acid salts of lead, lead oxide and lead hydroxide), copper compounds (such as copper fluoride, copper chloride, copper bromide, copper iodide, copper nitrate, copper sulfate, copper perchlorate, copper carbonate and like inorganic salts of copper, copper acetate, copper oxalate and like fatty acid salts of copper, copper oxide and copper hydroxide), titanium compounds (such as titanium fluoride, titanium chloride, titanium bromide, titanium iodide, titanium nitrate and titanium sulfate), bismuth compounds (such as bismuth fluoride, bismuth chloride, bismuth bromide, bismuth iodide, bismuth nitrate, bismuth sulfate and bismuth oxide), antimony compounds (such as antimony fluoride, antimony chloride, antimony bromide and antimony iodide). Among these metals, preferable is lead compound.
These metal compounds are used usually in an amount of 0.001 to 10 moles, preferably 0.01 to 3 moles, per mole of the compound of the formula (1).
When at least two of these metallic compounds are used in combination, it is accordingly desirable to use each of at least two metallic compounds in the amount mentioned above.
Examples of combinations each comprising a metal up to xe2x88x920.3 (V/SCE) in standard oxidation reduction potential and a compound of a metal having a higher standard oxidation reduction potential than the metal are aluminum/lead compound, aluminum/bismuth compound, manganese/aluminum compound, manganese/lead compound, zinc/lead compound, magnesium/bismuth compound, magnesium/bismuth compound, magnesium/copper compound, tin/titanium compound, tin/bismuth compound, etc. The combination of aluminum/lead compound permits reduction to proceed smoothly and is therefore preferred.
Examples of useful solvents are dimethylacetamide (DMA), dimethylformamide, 1-methyl-2-pyrrolidinone (NMP), hexamethylphosphoric triamide and like amides, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile and like nitrites, dimethylimidazole (DMI), dimethyl sulfoxide, tetrahydrofuran (THF), dioxane, etc. These solvents may be used singly, or at least two of them may be used in mixture.
These solvents, each serviceable as the main solvent, can be used as mixed with other usual solvents, such as methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate and like lower alkyl esters of lower alkylcarboxylic acids, diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl cellosolve, dimethoxyethane and like ethers, tetrahydrofuran, dioxane and like cyclic ethers, benzene, toluene, xylene, chlorobenzene, anisole and like substituted or unsubstituted aromatic hydrocarbons, pentane, hexane, heptane, octane and like hydrocarbons, cyclopentane, cyclohexane, cycloheptane, cyclooctane and like cycloalkanes, dichloromethane, chloroform, dichloroethane, trichloroethane, dibromoethane, propylene dichloride, carbon tetrachloride, Freons and like halogenated hydrocarbons.
Especially preferable are solvent mixtures consisting primarily of diemthylformamide, 1-methyl-2-pyrrolidinone or dimethyl sulfoxide.
The water-containing organic solvents for use in preparing 3-norcephem compounds usually contains 0.2 to 75%, preferably 1 to 40%, of water.
It is desirable to use such solvents in an amount of about 0.5 to about 206 liters, preferably about 1 to about 50 liters, per kilogram of the compound of the formula (1).
The reaction is conducted usually at xe2x88x9210 to 80xc2x0 C., preferably 0 to 50xc2x0 C. The reaction of the invention proceeds favorable even at a temperature around room temperature.
The compound of the formula (3) to be obtained by the present invention can be prepared substantially as a pure product by treating the reaction mixture through a usual extraction procedure or crystallization procedure after the completion of reaction. The product can of course be purified alternatively by other method.
In the case where the compound prepared by the present invention is of the formula (3) wherein R1 is protected amino, and R2 is a hydrogen atom [compound (3-1)], this compound is subjected to an amino deprotecting reaction disclosed, for example, in Recent Advances in the Chemistry of xcex2-Lactam Antibiotics, 109 (1980), whereby a 7-amino-3-cephem compound (3-2) can be derived. It is of course possible to derive the 7-amino-3-cephem compound (3-2) directly from a compound of the formula (1) wherein R1 is amino, and R2 is a hydrogen atom by the process of the invention 
wherein R3 and R5 are as defined above, and R is a protective group for the amino.
The 7-amino-3-cephem compound (3-2) obtained is used as an important intermediate for preparing useful antimicrobial drugs having a wide antibacterial spectrum.
For example, a compound (3-2) wherein R5 is vinyl can be made into the oral antibiotic cefixime by the process disclosed in JP-B-20435/1988, or the compound (3-2) can be made into cefdinir (Katsuharu Sakai, xe2x80x9cHandbook of Recent Antibiotics,xe2x80x9d 9th ed., p. 86, 1994).
Furthermore, the oral antibiotic ceftibuten can be derived from a compound (3-2) wherein R5 is a hydrogen atom by the process disclosed in Pure and Appl. Chem., 59, 1041 (1987).
According to the invention, the substituents of R1, R2 and R3 in the compound of the formula (1) do not participate in the reaction, permitting the reaction to proceed regardless of the kind thereof and affording a compound of the formula (3) which can be used as an intermediate for preparing useful nonnatural antimicrobial drugs.